We have demonstrated that a stable, mutant cell line of human malignant lymphoblastic leukemic origin made resistant to MTX (CEM/MTX) owes its resistance to a defect in uptake of MTX ("membrane resistance") as compared with the parent, MTX-sensitive CEM cell line. Availability of this unique cell line makes possible approaches to the therapy of MTX-resistant human malignancies by alternative antifolates, and hopefully circumvention of MTX resistance. Establishment of the CEM/MTX cell line in the nude mouse will permit an in vitro/in vivo comparison of therapeutic approaches. CEM lines resistant to other antifolates,aminopterin and DDMP, are also available. Comparable studies will also be conducted with a CEM cell line made resistant to adriamycin (CEM/ADR) to permit a similar approach to the therapy of adriamycin-resistant human malignant cells. It is planned to generate a CEM cell line resistant to actinomycin D.